Manufacture of p-alkoxysalicylic acids



Patented F eb. 16, 1954 MANUFACTURE OF D-ALKOXYSALICYLIC ACIDS Robert S.Long, Bound Brook, N. J., and Nancy P. Buckwalter, Philadelphia, Pa.,assignors to American Cyanamid ,Company, New York, N. Y., a corporationof Maine No Drawing. Application July 11, 1951, Serial No. 236,284

3 Claims.

The present invention relates to the preparation of p-alkoxysalicylicacids of the formula COOH RO OH in which R is a lower alkyl radical.

The alkoxysalicylic acids are important intermediates for thepreparation of fluorescent textile brighteners and other products.Formerly, these intermediates were prepared by monoalkylating resolcylicacid. These processes have some disadvantages and require the use ofresorcin which is often in short supply as it is a strategic rawmaterial. According to the present invention, the alkoxysalicylic acidsare produced by the diazotization of p-aminosalicylic acid andsubsequent alcoholysis. The diazotiazation of p-aminosalicylic acid, andreplacement of the diazonium radical, is not a simple operation. Ifcarried out by the conventional procedures, impure products contaminatedwith colored impurities result, and the yields are entirelyunsatisfactory.

The present invention is directed to a simple and eflicient method ofpreparing p-alkoxysalicylic acid from p-aminosalicylic acid. The processinvolves diazotization by a particular method and alcoholysis with analcohol corresponding to the alkoxy radical desired. The diazotizationprocedure requires that the p-aminosalicylic acid and alkali metalnitrite be added to a mineral acid solution. The p-aminosalicylic acidand alkali metal nitrite may be added separately as solids. Preferably,a salt of paminosalicylic acid, such as an alkali or alkaline earthmetal salt, is first dissolved in water, alkali metal nitrite is added,and the mixed aqueous dispersion is added to a mineral acid to effectdiazotization. The mineral acid, of course, transforms the nitrite andp-aminosalicylate into the free acids at the moment of diazotization. Inthis manner side reactions and the production of colored impurities arereduced to negligible amounts or eliminated entirely.

The process of the present invention may be carried out in one of twomodifications as a 2 step or single step process using the term step todesignate an actual sequence of operations rather than a sequence ofchemical reactions. In the 2-step process, diazotization of thepaminosalicylic acid is effected as described above at low temperatureproducing the diazonium salt which can be isolated as a solid and addedto hot alcohol to effect alcoholysis. The second modification involves asingle reaction mixture and it, in turn, has 2 variants. In the first,the nitrite and p-aminosalicylic acid or its salt are added to a coldmineral acid alcohol solution containing not more than 35% of waterbased on the alcohol. The alkoxyl group is then introduced by heatingthe solution. The second variant is to add p-aminosalicylic acid to thealcoholic solution of the mineral acid and diazotize by adding thenitrite at an elevated temperature so that the diazo compound isalcoholized as fast as it is formed. Not only does this latter processsave steps, but the control of the diazotization is improved because thepresence of the alcohol appears to inhibit, to some extent, sidereactions. The exact mechanism whereby the alcohol prevents undesiredside reactions is not completely determined and the invention is notlimited to any theory of how this takes place.

The alcohols used may be any of the lower alkanols such as methanol,ethanol, propanols, butanols, the various amyl alcohols, and the like.It is an advantage of the invention that a wide variety of lower alkoxyradicals may be introduced into the salicylic acid molecule'by a simpleand smooth reaction. The amount of water in the reaction mixture at thetime of alcoholysis must be limited. In any event, it must not exceed35%. However, for best results, considerably smaller concentrations ofwater are preferable. :So long as the upper limit is not exceeded theexact amount of water is not critical and this is an advantage of theprocess and it makes ex tremely delicate control of the inventionunnecessary.

Any of the ordinary mineral acids may be used, such as hydrochloricacid, sulfuric acid, phosf phoric acid, etc. When the diazotization isef fected in alcohol solution it is advantageous to use dry hydrogenchloride in order to avoid introducing excessive amounts of water intothereaction mixture. i

It is not known why the adverse efiect of the halide ion is not quite somarked in the present invention as when replacement of the diazoniumgroup by nydroxyl is effected. This constitutes an advantage as it givesmorefreedom of choice of reactants.

Regardless of the particular modification used, the reaction proceedssmoothly and the final product, p-alkoxysalicylic acid, is readilyisolated by conventional means. Thus, the alcohol can be distilled oil"and the residue extracted with alkali followed by acidification toprecipitate the product, which is of high purity and is obtainable ingood yield.

The amount of alcohol required in the present invention is in nowisecritical. Obviously, of course, enough alcohol must be present tofurnish the alkoxy radical and this constitutes a lower limit. However,it is desirable to operate with an excess of alcohol. This insurescompletion of the reaction and permits more rapid alcoholysis andincreased output from a given equipment. The amount of excess of alcoholis not critical but, of course, enormous excesses do not produce anyimproved results and, therefore, are economically undesirable.

The invention will be described in greater detail in conjunction withthe following specific examples, all parts being by weight unlessotherwise specified.

Example 1 A mixture of 30.6 parts of p-aminosalicylic acid and 5.0 partsof concentrated hydrochloric acid in 400 parts of methanol is dilutedwith 258 parts of water. The resulting solution is heated to 60-65?" and14.0 parts of sodium nitrite dissolved in 20 parts of water is addedgradually. After the, addition the methanol is distilled oil; Theresidue is cooled, and filtered to give the desired p-methoxy salicylicacid.

Example 2 A mixture of 30.6 parts of p-arninosallcylic acid and 25 partsof concentrated hydrochloric acid in 400 parts of methanol is heated toreflux. There is then gradually added a solution of 14.0 parts of sodiumnitrite in 20 parts ofwater. The addition is so governed that the diazocompound reacts as fast as it is formed, as shown by a negative colorreaction with a coupling component, such as R salt, throughout thecourse of the addition.

The methanol is distilled out of the reaction mixture, which is thendigested with aqueous bicarbonate. The resulting solution is filteredand acidified, giving a good yield of p-methoxysalicyli'c acid.

Example 3 Example 4 To a solution of 30.6 parts of p-aminosalicylic acidand 54 parts of 5 N sodium hydroxide in 50 parts of water, there isadded a solution of 140 parts of sodium nitrite in 20 parts of water.This solution is added gradually to a vigorously refluxing solution of50 parts of concentrated hydrochloric acid in 160 parts of methanol. Therate of addition is so governed that no excess diazocompound accumulatesin the methanol solution. When the addition is complete, the mixture isevaporated to remove the remaining methanol. The solids thus obtainedare digested inaqueoussodium bicarbonate, the resulting solutiorrbeingfiltered and acidified with hydrochloric (iii 4 acid. A good yield ofp-methoxysalicylic acid is obtained.

Example 5 A solution of 30.6 parts of p-aminosalicylic acid in 400-partsof methanol is cooled to 0 C. There is then added, with cooling to keepthe temperature between 0 and 10 C., 29.4 parts of sulfuric acid. To theresulting slurry is gradually added, at a temperature below 5 C. asolution of 14.0 parts of sodium nitrite in 20 parts of water. Themixture is then brought to room temperature, diluted with 200 parts ofwater, heated to the boil, freed of methanol by distillation, madealkaline with sodium bicarbonate and filtered. Acidification withhydrochloric acid precipitates p-methoxysalicylic acid, which isfiltered and dried.

Example 6 A solution is prepared from 30.6 parts of paminosalicylic.acid, '70 parts of water, 54 parts of 5N sodium hydroxide solution, and14.0 parts of sodium nitrite. This is added gradually to 175 parts of 35hydrochloric acid at 0 C. The resulting slurry of diazo compound issalted with 10 parts of sodium chloride to further completeness ofprecipitation, and then filtered at 0 C. The product is added to 200parts of boiling methanol, and refluxed until the diazo compound iscompletely consumed as shown by the failure togive any reaction with acoupling component.

The reaction mixture is evaporated, and extracted with sodiumbicarbonate solution. Acidification gives the desired p-methoxysalicylicacid, which is filtered and dried.

Example 7 A solution. of 29.4 parts of 100% sulfuric acid in parts ofmethanol is cooled to -5 C. To this solution is added gradually andsimultaneously a solution of 30.6 parts of p-amincsalicylic acid in 240parts of hot methanol, and a solution of 14.0 parts of sodium nitrite in20 parts of water. During this opertaion the temperature is maintainedbelow 5 C. The reaction mixture is then brought to room. temperature,diluted with 200 parts, of water, heated to the boil, and distilled toremove the methanol. The residue is cooled, filtered, dissolved inaqueous sodium bicarbonate, filtered with decolorizing charcoal, andacidified to precipitate the pmethoxysalicylic acid.

Example 8 The procedure of the preceding example is followed, exceptthat the sulfuric acid is replaced by 50 parts of concentratedhydrochloric acid. Essentially similar results. are obtained.

Example 9 To a solution of 30.6 parts of p-aminosalicylic acid in 400parts of methanal there is added 50 parts of concentrated hydrochloricacid. The resulting mixture is cooled to 0 C. and gradually treated with14.0 parts of ground sodium nitrite. No excess of nitrite is presentuntil the end of the reaction. The mixture is thoroughly stirred at 0 C.and then gradually brought to room temperature.

The reaction mixture is brought to the boil and freed oi the greaterpart of the methanol by distillation. The residue is cooled andfiltered. giving a very high yield of p-methoxysalicylic acid.

Example 10 To a mixture of 30.6 parts of p-aminosalicylic acid and 24parts of N sodium hydroxide solution is added 208 parts of N sodiumnitrite solu tion. This is followed by an additional 24 parts of 5Nsodium hydroxide, together with a few crystals of sodium hydrosulfite todischarge any red color which develops. This solution is gradually addedat 0-5 to a solution of 62 parts of 964% sulfuric acid in 31 parts ofwater and the brown solution so obtained is added to 790 parts ofboiling methanol. The resulting vigorous reaction rapidly consumes thediazo compound. The bulk of the remaining methanol is distilled off. Theresidue is cooled, filtered, dissolved in sodium bicarbonate solution,filtered with decolorizing charcoal, and acidified to precipitate thep-methoxysalicylic acid.

We claim:

1. A process of producing a p-lower alkoxysalicylic acid which comprisesintroducing simultaneously p-aminosalicylic acid and a nitrite into alower alkanol solution of mineral acid maintained at a temperaturegreater than 60 0., the reaction mixture containing not more than 35% byweight of water based on the lower alkanol.

2. A process of producing a p-methoxysalicylic acid which comprisesintroducing simultaneously p-aminosalicylic acid and a nitrite into amethanol solution of mineral acid maintained at a temperature greaterthan 60 C., the reaction mixture containing not more than by weight ofwater based on the methanol.

3. A process of producing a p-ethoxysalicylic acid which comprisesintroducing simultaneously p-aminosalicylic acid and a nitrite into anethanol solution of mineral acid maintained at a temperature greaterthan C., the reaction mixture containing not more than 35% by weight ofwater based on the ethanol. 1

ROBERT S. LONG. NANCY P. BUCKWALTER.

References Cited in the file of this patent UNITED STATES PATENTS NameDate Shildneck Feb. 15, 1949 FOREIGN PATENTS Country Date Great BritainFeb. 2, 1945 OTHER REFERENCES Number Number

1. A PROCESS OF PRODUCING A P-LOWER ALKOXYSALICYLIC ACID WHICH COMPRISESINTRODUCING SIMULTANEOUSLY P-AMINOSALICYLIC ACID AND A NITRITE INTO ALOWER ALKANOL SOLUTION OF MINERAL ACID MAINTAINED AT A TEMPERATUREGREATER THAN 60* C., THE REACTION MIXTURE CONTAINING NOT MORE THAN 35%BY WEIGHT OF WATER BASED ON THE LOWER ALKANOL.